A prospective exploration of symptom burden clusters in women with breast cancer during chemotherapy treatment.

PURPOSE: The aim was to prospectively map symptom clusters in patients with stage I-IIIa breast cancer during standard chemotherapy treatment in a randomised study. METHODS: Participants completed the Memorial Symptom Assessment Scale (MSAS) at baseline, day 12 after the first and third cycle of FEC 75 or FEC 100, and day 12 after the last cycle of Taxotere. Cut-off values for symptom scores, a mean value based on each individual reporting a symptom including occurrence, frequency, severity and distress for inclusion in analysis, were determined. RESULTS: The symptom burden cluster analysis was conducted in two steps and included symptoms with high frequency and high levels of distress. The factor analysis revealed three symptom clusters; physical, gastro (phys/gastro) and emotional, with core symptoms that remained stable over time. The most prevalent symptoms for the total sample during all cycles were as follows: lack of energy (range between 48 and 90%), feeling sad (48-79%), difficulty sleeping (54-78%), difficulty concentrating (53-74%), worrying (54-74%) and pain (29-67%). CONCLUSION: In summary, we have prospectively established that symptom clusters remain stable over time with a basis of core symptoms. This knowledge will aid in the development of effective core symptom-focused interventions to minimise symptom burden for patients treated with chemotherapy for breast cancer.

Novel octabrominated phenolic diphenyl ether identified in blue mussels from the Swedish West Coast.

Hydroxylated (OH-) and methoxylated (MeO-) polybrominated diphenyl ethers (PBDEs) are compounds present in the marine environment and OH-PBDEs are of toxicological concern and are therefore of interest to monitor in the environment. A phenolic octaBDE was tentatively identified in the phenolic fraction of previously analyzed mussel samples after methylation of the halogenated phenolic compounds (HPCs). The aim of the present study was to confirm the identity of this compound in blue mussels and investigate whether the analyte is diOH- and/or OH-MeO-octaBDE. Two reference standards, 6,6'-dimethoxy-2,2',3,3',4,4',5,5'-octabromodiphenyl ether (6,6'-diMeO-BDE194) and 6-ethoxy-6'-methoxy-2,2',3,3',4,4',5,5'-octabromodiphenyl ether (6-EtO-6'-MeO-BDE194) were prepared via O-arylation of 2,3,4,5-tetrabromo-6-methoxyphenol and 2,3,4,5-tetrabromo-6-ethoxyphenol, respectively, with a novel unsymmetrical diaryliodonium salt, 2,3,4,5-tetrabromo-6-methoxydiphenyliodonium triflate. The GC retention time and GC/MS spectrum of the synthesized 6,6'-diMeO-BDE194 correspond well with the analyte in the methylated phenolic fraction of a mussel extract from a previous study. Structural analysis performed in this study indicate that the synthesized 6,6'-diMeO-BDE194 and 6-EtO-6'-MeO-BDE194 correspond well with 6-hydroxy-6'-methoxy-2,2',3,3',4,4',5,5'-octabromodiphenyl ether (6-OH-6'-MeO-BDE194) after methylation and ethylation, respectively, of the HPCs in the mussel extracts. The compound 6-OH-6'-MeO-BDE194 was identified and quantified in new mussels, sampled in 2012 from two locations on the Swedish west coast, with geometric mean concentrations of 3700 and 410 ng/g fat, respectively.

Human hydroxylated metabolites of BDE-47 and BDE-99 are glucuronidated and sulfated in vitro.

Polybrominated diphenyl ethers (PBDEs) were used worldwide as additive flame retardants and are classified as persistent, bioaccumulable and toxic environmental pollutants. In humans, the hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) formed in vitro have also been detected in vivo. To further characterize the metabolism of BDE-47 and BDE-99 and to identify candidate markers for monitoring the human exposure to PBDEs using non-invasive approaches, glucuronidation and sulfation of hydroxylated metabolites of BDE-47 and BDE-99 were investigated using human liver microsomes and cytoplasm, respectively. The formed Phase II metabolites were analyzed by liquid chromatography-tandem mass spectrometry using a novel approach to develop analytical methods in absence of authentic standards. All available standards for hydroxylated metabolites of BDE-47 and BDE-99 were glucuronidated and sulfated, showing that glucuronidation and sulfation are part of the metabolism pathway of BDE-47 and BDE-99 in vitro. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-47 were (a) 2,4-DBP-Gluc and 5-Gluc-BDE-47, and (b) 2'-Sulf-BDE-28, 4-Sulf-BDE-42 and 3-Sulf-BDE-47, respectively. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-99 were (a) 2,4,5-TBP-Gluc and 6'-Gluc-BDE-99, and (b) 3'-Sulf-BDE-99 and 5'-Sulf-BDE-99, respectively. Apparent Km values associated with the formation of sulfated metabolites of BDE-47 and BDE-99 were ten times lower than those of the corresponding glucuronidated metabolites, suggesting that sulfated rather than glucuronidated metabolites of OH-PBDEs might be used as markers of human exposure to PBDEs using a non-invasive approach based on urine sample collection.

Validation of a novel procedure for quantification of the formation of phosphoramide mustard by individuals treated with cyclophosphamide.

PURPOSE: Use of the patient's body surface area (mg m(-2)) as a basis for dosing does not take individual variation in metabolic capacity and rate of clearance into account. Here, we evaluated a novel approach for individual monitoring of short-lived cytotoxic agents formed from cytostatic drugs such as cyclophosphamide (CP). METHODS: The accumulated blood dose of the cytotoxic active agent phosphoramide mustard (PAM) formed from CP was measured as a reaction product with hemoglobin (Hb adduct). This adduct, N-[2-(2-oxazolidonyl)ethyl]-valyl Hb (OzVal-Hb), was detached from Hb with the adduct FIRE procedure™, and the formed analyte was quantified using LC-MS/MS. This dose biomarker for PAM and the analytical procedure was evaluated in accordance with the guidelines on bioanalytical method validation formulated by the European Medicine Agency. The evaluated method was applied to quantify blood dose levels of PAM in female breast cancer patients (n = 12) before and after three cycles of polychemotherapy regimes containing CP. RESULTS: OzVal-Hb, a specific and stable biomarker, could be measured with great sensitivity (lower limit of quantification = 33 pmol g(-1) Hb), high accuracy (within ±20 %) and good repeatability (CV < 20 %). The inter-individual variability in the blood level of this adduct in women with breast cancer (n = 12) who received three doses of CP in combination with one or two other cytostatic drugs was 250 % following the first dose and approximately 150 % after each subsequent dose. CONCLUSIONS: Measurement of the biomarker OzVal-Hb can be used to quantify the short-lived cytotoxic agent PAM in a single blood sample drawn several days after therapy. This procedure may aid in individualizing doses of CP, thereby improving efficacy while both reducing the risk of and increasing the predictability of side-effects.

Synthesis and tentative identification of novel polybrominated diphenyl ether metabolites in human blood.

Hydroxylated polybrominated diphenyl ethers (OH-PDBEs) are exogenous, bioactive compounds that originate, to a large extent, from anthropogenic activities, although they are also naturally produced in the environment. In the present study nine new authentic OH-PBDE reference standards and their corresponding methyl ether derivatives (MeO-PBDEs) were synthesised and characterised by NMR spectroscopy and mass spectrometry. Seven of the authentic reference standards prepared were thereafter tentatively identified in a pooled human blood sample. The tentatively identified OH-PBDEs were 3-hydroxy-2,2',4,4',6-pentabromodiphenyl ether, 3'-hydroxy-2,2',4,4',6-pentabromodiphenyl ether, 3-hydroxy-2,2',4,4',5-pentabromodiphenyl ether, 3-hydroxy-2,2',4,4',5,6'-hexabromodiphenyl ether, 3'-hydroxy-2,2',4,4',5,6'-hexabromodiphenyl ether, 3-hydroxy-2,2',4,4',5,5'-hexabromodiphenyl ether and 4-hydroxy-2,2',3,4',5,5',6-heptabromodiphenyl ether. An additional seven OH-PBDEs were tentatively identified in the pooled human blood sample, of which one OH-PBDE, 4'-hydroxy-2,2',4,5,5'-pentabromodiphenyl ether, has not been identified in human blood before. The identification was performed using gas chromatography-mass spectrometry (GC-MS) recording the bromine ions m/z 79, 81. The tentative identification was supported by the peaks relative retention times (RRTs) compared to authentic references on two GC columns of different polarities for the hexa-, and heptabrominated OH-PBDEs, and three different GC columns for the pentabrominated OH-PBDEs. The OH-PBDE congeners most likely originate from human metabolism of a flame retardant, i.e. polybrominated diphenyl ethers (PBDEs), due to the relatively high concentrations of PBDEs in the same human blood sample and the fact that these PBDEs could form the tentatively identified OH-PBDEs via metabolic direct hydroxylation or via 1,2-shift.

A novel abbreviation standard for organobromine, organochlorine and organophosphorus flame retardants and some characteristics of the chemicals.

Ever since the interest in organic environmental contaminants first emerged 50years ago, there has been a need to present discussion of such chemicals and their transformation products using simple abbreviations so as to avoid the repetitive use of long chemical names. As the number of chemicals of concern has increased, the number of abbreviations has also increased dramatically, sometimes resulting in the use of different abbreviations for the same chemical. In this article, we propose abbreviations for flame retardants (FRs) substituted with bromine or chlorine atoms or including a functional group containing phosphorus, i.e. BFRs, CFRs and PFRs, respectively. Due to the large number of halogenated and organophosphorus FRs, it has become increasingly important to develop a strategy for abbreviating the chemical names of FRs. In this paper, a two step procedure is proposed for deriving practical abbreviations (PRABs) for the chemicals discussed. In the first step, structural abbreviations (STABs) are developed using specific STAB criteria based on the FR structure. However, since several of the derived STABs are complicated and long, we propose instead the use of PRABs. These are, commonly, an extract of the most essential part of the STAB, while also considering abbreviations previously used in the literature. We indicate how these can be used to develop an abbreviation that can be generally accepted by scientists and other professionals involved in FR related work. Tables with PRABs and STABs for BFRs, CFRs and PFRs are presented, including CAS (Chemical Abstract Service) numbers, notes of abbreviations that have been used previously, CA (Chemical Abstract) name, common names and trade names, as well as some fundamental physico-chemical constants.